The mechanism by which analogs and antagonists of the dicarboxylic amino acids and their amides exert toxic and oncolytic effects have been examined with animals, cells in culture, and isolated enzymes. In addition, the mechanisms by which cells become resistant to the toxic or therapeutic actions of these agents have been studied, using resistant variants of transplantable murine tumors growing in vivo and in vitro. In various lines resistance to PALA correlates with elevated levels of L-Aspartic acid Transcarbamylase; however, in at least one resistant variant of the Lewis Lung Carcinoma, resistance is accompanied by increased Carbamyl Phosphate Synthetase II. The locus of action of Acivicin has not yet been characterized, but resistance to this drug is clearly a transport-related phenomenon. In the case of L-Alanosine, resistance has been shown to be due to two factors; 1. an inability to synthesize and/or retain, critical concentrations of the proximate antimetabolite, 'L-Alanosyl-AICOR'; 2. higher basal levels of purine salvage enzymes in the resistant cell.